2021 Spring Prime Therapeutics Report

IN THIS ISSUE | Spring 2021

Published By

Magellan Rx Management 15950 N. 76th St. Scottsdale, AZ 85260

Tel: 401-344-1000 Fax: 401-619-5215 magellanrx.com

Editor Lindsay Speicher, J.D. Project Manager, Magellan Method lspeicher@magellanhealth.com 401-344-1105

Advertising, Sales and Distribution

Carole Kallas ckallas@magellanhealth.com 401-344-1132

The content of Magellan RxTM Report — including text, graphics, images, and information obtained from third parties, licensors, and other material (“content”) — is for informational purposes only. The content is not intended to be a substitute for professional medical advice, diagnosis, or treatment. Magellan RxTM Report does not verify any claims or other information appearing in any of the advertisements contained in the publication and cannot take responsibility for any losses or other damages incurred by readers in reliance on such content. Developed by D Custom.

Contributors

Caroline Carney, M.D., M.Sc., FAPM, CPHQ CMO, Magellan Health

Steve Cutts, Pharm.D. SVP, Market General Manager, MRx Specialty

Haita Makanji, Pharm.D. VP, Clinical Strategy and Innovation, Specialty

Misty Grefcz Director, Marketing

Joe Tavares SVP, Sales and Business Development, Specialty

Corrado Panno VP, Business Development, Magellan Method

Stacy Inman, Pharm.D.

Senior Clinical Project Manager, Magellan Method

Alex Baratz

Senior Director, Clinical Project & Program Management

Carole Kallas

Project Manager

Brian Kinsella, Esq.

Senior Legal Counsel

Alina Young Associate Legal Counsel

Lilly Ackley VP, Corporate Communications

Kristen Durocher Director, External Communications

Editorial Advisory Board

Mona M. Chitre, Pharm.D., CGP

Chief Pharmacy Ofcer & VP Clinical Analytics, Strategy & Innovation, Excellus BlueCross BlueShield

Dennis Bourdette M.D., FAAN, FANA

Chair and Roy and Eulalia Swank Family Research Professor, Department of Neurology, Oregon Health & Science University

Yousaf Ali M.D., FACR

Chief, Division of Rheumatology, Mount Sinai West; Professor of Medicine, Icahn School of Medicine at Mount Sinai

Steven L. D’Amato, B.S.Pharm. Executive Director, New England Cancer Specialists

Joseph Mikhael M.D., M.Ed., FRCPC, FACP

Chief Medical Ofcer, International Myeloma Foundation

Natalie Tate, Pharm.D., MBA, BCPS Vice President, Pharmacy Management, BlueCross BlueShield of Tennessee

Steve Marciniak, R.Ph.

Director II, Medical Beneft Drug Management, BlueCross BlueShield of Michigan

Saira A. Jan, M.S., Pharm.D.

Director of Pharmacy Strategy and Clinical Integration, Horizon BlueCross BlueShield of New Jersey

A NOTE FROM OUR CMO

Dear Managed Care Colleagues,

Welcome to our spring 2021 issue of the Magellan Rx Report! his year is o to an exciting start following the U.S. Food and Drug Administration’s (FDA) issuance of emergency use authorization for two COVID-19 vaccines at the end of 2020 and an additional authorization issued in late February. While COVID-19 is still very much at the forefront, we are seeing advancements in other healthcare spaces as well. So far this year, the FDA has already approved 14 novel therapies, with several more in the queue for the remainder of 2021. Magellan Rx Management is committed to keeping our readers informed with timely content focused on the ongoing global health crisis, as well as other important clinical advances and managed care trends.

Our cover story (page 22) highlights the changing treatment landscape of multiple myeloma, including the emergence of CAR-T therapies and the anticipated impact on managed care.

A feature article focuses on the impact of COVID-19 on the delivery of care and how the increased use of telehealth and home care may change healthcare in a post-pandemic world (page 4).

We outline mental health updates in another story (page 17), in which we discuss the utility and opportunities presented by digital therapeutics in mental health, the robust pipelines across mental health indications, and the current and long-term impact COVID-19 has had on mental health.

In another article, we discuss the treatment landscape of wet age related macular degeneration, s ecifcally focusing on the introduction of biosimilars in this market and the potential impact on all stakeholders (page 13).

Other timeline topics in this issue include a look at management of the rare neuromuscular disease space (page 28) and the impact of IV iron on managed care (page 33). As always, the issue is rounded out with our pipeline update (page 38) and managed care newsstand (page 2).

To learn more about Magellan Rx Management and our support for payer initiatives of the future, please feel free to contact us at MagellanRxReport@magellanhealth.com. As always, we value any feedback you may have. I hope you enjoy the report!

Sincerely,

Caroline Carney, M.D., M.Sc., FAPM, CPHQ Chief edical cer Magellan Health & Magellan Rx Management

Stay on top of managed care trends and become a Magellan Rx Report subscriber. Email us at MagellanRxReport@magellanhealth.com to subscribe today. Magellan Rx Report provides pharmacy and medical management solutions for managed care executives and clinicians. We hope you enjoy the issue; thank you for reading.

MANAGED CARE

NEWSSTAND

President Biden Sworn In as 46th President and COVID-19 and Healthcare Among Top Priorities

President Biden was sworn in as the nation’s 46th president on Jan. 20. Addressing the COVID-19 pandemic and healthcare challenges are top priorities as he egins his term in ofce On March , the president signed into law a sweeping $1.9 trillion COVID-19 relief package, which immediately ro ided , stimulus ayments to more than of indi iduals and families he ill also ro ides illion in aid to states and localities, more than illion to hel reo en schools, and additional illions to accelerate accination and testing across the country Additionally, the ill includes a signifcant increase in funding for mental health and addiction ser ices

In addition to the recently signed stimulus ac age, President Biden issued executi e orders on his frst day in ofce, including directing that mas s e worn in all federal facilities, re oining the orld Health Organization, and creating a COVID-19 response coordinator as the hite House mo es to assert a more national strategy to fght the andemic On Jan , he issued another executi e orders hese include esta lishing community accination centers across the country, ex anding accine roduction and ersonal rotecti e e ui ment a aila ility through the Defense Production Act, and re uiring mas s to e worn at all airports and other transportation facilities as well as during tra el on lanes, trains, and uses and on all federal ro erty he orders also re uire testing for all international tra elers and direct that federal agencies uic ly es-

tablish guidance for schools during the andemic he resident has stated that his goal is to ha e million eo le accinated within days He also issued a num er of executi e orders on Jan addressing the A orda le Care Act ACA as art of his e ort to uild and strengthen this landmark legislation that was assed when he ser ed as ice president.

he administration also announced on Jan. 20 a freeze on all regulations that ha e not yet ta en e ect his is a common step a new administration takes when assuming ofce, as it allows the new administration to re iew any of the last minute rules the re ious administration issued he guidance calls for agencies to re iew ending rules and to recommend whether the rules should e delayed for u to days ending further re iew, including ta ing action to see additional u lic comment his action does not automatically mean all rules will e frozen here are a num er of rules that ha e not yet een fnalized, including the rum administration rules to eliminate rebates in the Part D program, to esta lish Most Fa ored Nation drug ricing, or to im lement changes to rior authorization, among others

Rebate Rule Delayed

In res onse to litigation rought y the Pharmaceutical Care Management Association challenging the Medicare Part D re ate rule, the Biden administration agreed to ost one the e ecti e date of the ro isions of the rule relating to the elimination of the regulatory discount safe har or for retros ecti e re ates from Jan , , to Jan ,

Judge John D. Bates of the U.S. District Court for the District of Columbia entered an order memorializing the agreement signed Jan to ost one all ro i-

sions” of the Rule “that were scheduled to ta e e ect on Jan , until Jan , , holding the case in a eyance during HHS re iew of the rule su ect to the continued consent of the arties, and calling for a oint status re ort not later than A ril ,

his agreement follows closely on the heels of the HHS OIG, delaying certain ro isions of the re ate rule, including a new safe har or for ser ice fees that manufacturers ay to PBMs to March , hese ro isions are not a ected y the legal order

President Biden Issues Executive Order to Strengthen Medicaid

On Jan , President Biden issued an xecuti e Order on Strengthening Medicaid and the A orda le Care Act he executi e order directs the heads of agencies to re iew existing regulations, orders, guidance documents, olicies, and any other similar agency actions that limit access to healthcare and consider actions to strengthen access to care through Medicaid and ACA he executi e order esta lishes that it is the administration s olicy to rotect and strengthen Medicaid and ACA and to ma e high uality healthcare accessi le and a orda le for e ery American S ecifcally, as art of this re iew, the order directs agencies to examine:

Policies or ractices that may undermine protections for people with re existing conditions, including com lications related to COVID , under ACA.

Demonstrations and wai ers, as well as olicies that may reduce co erage under or otherwise undermine Medicaid or ACA.

Policies or ractices that may undermine the Health Insurance

Mar et lace or the indi idual, small grou , or large grou mar ets for health insurance in the U.S. Policies or ractices that may resent unnecessary arriers to indiiduals and families attem ting to access Medicaid or ACA co erage, including for midyear enrollment Policies or ractices that may reduce the a orda ility of co erage or fnancial assistance for co erage, including for dependents.

Agencies must consider whether to susend, re ise, or rescind such olicies or actions that are inconsistent with the administration s olicy identifed in the executi e order and consider additional actions to strengthen and protect access to care.

Additionally, the order s ecifcally reo es two rum administration actions xecuti e Order , Minimizing the Economic Burden of Patient Protection and A orda le Care Act Pending e eal, and xecuti e Order , Promoting Healthcare Choice and Competition across the nited States, which led to rulema ing to ex and short term, limited duration lans, association health lans, and Health eim ursement Arrangements he agencies are directed to re iew olicies stemming from these orders.

CMS Moves to Rescind Medicaid Work Requirements

On Fe , Centers for Medicare and Medicaid Ser ices CMS Acting Administrator Cheri ichter sent letters to seeral states announcing CMS is beginning a process to determine whether to withdraw their a ro ed wor re uirements demonstration wai er nder the rum administration, CMS granted aro als of wai ers to eight states that would allow them to implement

a contro ersial rum era rule that reuires Medicaid enefciaries to wor in order to recei e co erage he letters are the frst ste in unwinding the rule CMS will ro ide states with a written notice and an o ortunity to re uest a hearing before determining whether to susend, modify, or withdraw the wai ers

According to the aiser Family Foundation, eight states ha e een a ro ed for wor re uirement wai ers, se en ha e a lications ending, and four are waiting for court decisions. CMS’ action follows an executi e order issued y President Biden in January as ing agencies to consider actions that could strengthen and protect healthcare access.

X-Waiver Guidance Rescinded Telehealth

Clinical guidelines around treatment for opioid use disorder (OUD) announced in mid January under the rum administration were ulled ac y the Biden administration he guidance sought to remo e certain re uirements to o tain a wai er x wai er to rescri e urenor hine, which were seen as eyond the sco e of authority that the statute allowed.

Currently, the law allows hysicians to a ly for an x wai er to rescri e uprenorphine for the treatment of opioid addiction or dependence outside of an o ioid treatment rogram O P if certain re uirements are met e g , eight hours of training he x wai er re uirements which were meant to allow rimary care ro iders to treat O D are seen y many as a hurdle to treatment access

Exchanges Reopened for Special Enrollment Period

he federal Healthcare go xchange reopened for a three-month special

The executive order directs the heads of agencies to review existing regulations, orders, guidance documents, policies, and any other similar agency actions that limit access to healthcare and consider actions to strengthen access to care through Medicaid and the Aforda le Care Act.

enrollment eriod from Fe through May in order to allow those im acted y the andemic to sign u for coerage he De artment is committed to ensuring that we de loy e ery a aila le resource during the Public Health Emergency his S ecial nrollment Period will ensure more indi iduals and families ha e access to uality, a orda le health co erage during this un recedented time, said HHS Acting Secretary Norris Cochran.

COVID-19: Impact on Delivery of Care

The ongoing public health crisis has changed how care is delivered, with increasing utilization of telehealth and home care.

Lindsay C. Speicher, J.D. Project Manager Magellan Method

For the past year, the COVID-19 pandemic has transformed nearly every aspect of healthcare and healthcare delivery. Innovation was key in ensuring that patients received optimum care while remaining as safe and as healthy as possible. Particularly during times of high transmission rates and peak surges, close contact put patients, providers, and other healthcare professionals at high risk for exposure. Howe er, tools and inno ati e solutions allowed ro iders to treat atients in a safe, efcient way during this public health crisis.

Telehealth

Telehealth is a means for providers to use telecommunication technologies to provide care for patients without requiring physical proximity. Most commonly, patients and providers can have real-time appointments via video chat or on the phone. Other methods of telehealth include chat messaging, emailing, and remote patient monitoring. A wide variety of care can be provided via telehealth, including wellness visits, prescriptions, dermatology, eye exams, nutrition counseling, mental health counseling, and some urgent care conditions.

During the last week of March 2020, there was a 154% increase in telehealth visits from the same period in 2019.1 A 2020 survey reported that 79% of U.S. specialists said their use of telemedicine technology increased during the pandemic; fewer than half of cardiologists, gastroenterologists, pulmonologists, and respiratory specialists surveyed reported using telehealth prior to the pandemic.2 The survey reported that more than 75% of specialists would continue using virtual care technology in some capacity after the pandemic.2

Physicians are providing care via telehealth to between 50 and 175 times as many patients as they were prior to the pandemic.3, 4 While just 11% of patients reported using telehealth in 2019, around 46% of patients reported using telehealth to replace canceled in-person visits in 2020.3, 4 In a July 2020 survey, 40% of patients reported canceling upcoming appointments, and an additional 12% reported need-

ing care but not actively scheduling or receiving care.5 While the long-term impact of delayed care will vary depending on the condition and required maintenance, the impact and cost to the healthcare system could be substantial.5 Telehealth provides an alternative delivery method to maintain continuity of care as a solution for delayed preventive, chronic, or routine care. After the changes in healthcare delivery experienced in 2020, 57% of providers reported having a more favorable view of telehealth than they did before the pandemic, and 64% reported that they are more comfortable using it.3, 4

Due to the pandemic, the U.S. Centers for Medicare and Medicaid Services (CMS) has temporarily allowed telehealth to be used for more than 80 new services.3, 4 Many commercial payers have responded to COVID-19 by expanding access to telehealth services and in some cases waiving out-of-pocket costs for telehealth in order to provide members with safe opportunities to receive care.3, 4 This shift, however temporary, may result in strengthening patient and provider preferences for telehealth, embedding it in healthcare delivery.3, 4

Impact

Virtual visits could account for a quarter trillion, or about 20%, of what Medicare, Medicaid, and commercial payers spend on outatient, ofce, and home and health isits 4 In comparison, prior to 2020, telehealth accounted for only an estimated $3 billion.

here are f e models for irtual care 4

1. On-demand virtual urgent care: an alternative to some emergency department (ED) visits or urgent care visits.

2. irtual o ce visits an alternati e to in erson ofce consultations, during which physical exams or procedures are not required.

3. ear virtual o ce visits provides patients access to care outside a ro ider s ofce, com ining irtual hysician consultations with “near-home” sites for testing and immunizations.

4. irtual home health services virtual visits, remote monitoring, and digital patient-engagement tools can enable a portion of certain services to be delivered remotely, such as evaluations, patient and caregiver education, physical therapy, occupational therapy, and speech therapy.

5. Tech enabled home medication administration an alternative to outpatient infusible and injectable drug administration, which would leverage remote monitoring to help manage patients and monitor symptoms, provide patients with training for selfadministration, and use telehealth for o ersight of sta

Shifting these care o erings to telehealth could result in changes in the overall care-delivery system, including an avoidance of 20% of all D isits, irtual deli ery of of healthcare ofce isits and outpatient volume with an additional 9% delivered nearly virtually, virtualization of 35% of regular home health attendant services, and a 2% shift of all outpatient (OP) volume to the home setting with tech-enabled medical administration.3, 4 With the

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ongoing pandemic, these trends are expected to continue in the coming months (or longer). Virtual visits and telehealth could potentially account for about $250 billion of Medicare, Medicaid, and commercial s end on out atient isits, ofce isits, and home and health visits, while they only accounted for $3 billion prior to the pandemic.3, 4

This shift in care is not without challenges. Providers noted concerns around security, wor ow integration, reim ursement, and e ecti eness of telehealth isits as com ared to in erson isits 4 Additionally, while 76% of patients reported interest in telehealth, only 46% have actually used it, which could indicate a gap in patient education around telehealth availability and access.4

o ensure telehealth continues to o erate in an e ecti e manner after the pandemic, healthcare stakeholders can strategize accordingly by classifying patient populations whose remote interactions could be scaled up with home-based or virtual care and building capabilities of the clinician workforce to support virtual care.4

ome Infusion and are

Given the ongoing pandemic, site-of-care was a center point of discussion, with home infusion encouraged where appropriate. In April 2020, CMS released guidelines for the coverage of home infusion during the andemic, allowing exi ility for atients and providers to determine the best care solution for ongoing treatment.6 In the guidelines, CMS relaxed the defnition of

“homebound” to extend to at-risk patients who need to stay home to avoid COVID-19 exposure; CMS also relaxed the requirement for physician supervision in order to allow providers and clinics the exi ility to roaden the ser ices ty ically o ered in the home setting.6

Site-of-care initiatives have shown trends shifting toward home infusions S ecifcally, Penn Medicine launched Cancer Care at Home prior to the pandemic, in February 2020. However, during a seven-week period from March through April 2020, the program saw a 700% increase in home infusion referrals.7 Another initiative, headed by Option Care Health (“Option”), a company specializing in in-home infusion, aimed to support hospitals by assisting with the discharge of patients requiring infusion therapy.8, 9 Option reallocated a portion of its clinicians to areas with high rates of COVID-19 transmission to facilitate home infusion therapy.8, 9 Through this initiative, Option has worked with patients, respective payers, and hospitals to coordinate a safe discharge home and smooth transition to home infusion.8, 9 Strategies like these highlight the growing need to provide care in a safe home environment where appropriate, as well as the need for policies to integrate home care options.8, 9

Globally, the demand for home infusion therapies has increased in correlation to the pandemic — one report noted the market for home infusion is expected to hit $49.5 billion by 2027, growing at a compound annual growth rate of 11.7% during the pandemic.10 The market increased from $20.2 billion in 2019 to $22.9 billion in 2020, with growth attributed to the augmented adoption of home infusion treatment by chronic-disease patients due to COVID-19 risks.10

Impact

CMS partially acknowledged the trend toward home care in its fnal home health ayment rule, released in Octo er 11 In the rule, CMS estimated that Medicare payments to home health agencies will increase by $390 million.11 The National Home Infusion Association reported that there are currently 1,500 pharmacies across the S that o er infusion thera ies, illustrating a growth in demand over recent years.12

However, this trend toward home infusion and care has received criticism from some groups, such as the Community Oncology Alliance, which argues that home infusion for chemotherapy, cancer immunotherapy, and supportive drugs are not ideal, as home infusion “by a provider who may not be a trained oncology nurse and may not recognize or be prepared to treat any of the serious adverse reactions that frequently occur is of significant concern.”13

Globally, the demand for home infusion therapies has increased in correlation to the pandemic — one report noted the market for home infusion is expected to hit $49.5 billion by 2027, growing at a compound annual growth rate of 11.7% during the pandemic.

e t teps

Moving forward, the impact of the COVID-19 pandemic has paved the way for continued shifts in care-delivery trends. While CMS and commercial payers have expanded access to alternative modes of care delivery in light of the pandemic,14 it is uncertain whether this access will remain exi le or return to its re pandemic state.

If these shifts toward alternative care delivery continue even as the pandemic resolves, payers will likely focus on developing strategic initiati es to e ecti ely manage care and ensure that care options are available to appropriate patients. As noted, it will e essential to ensure that ualifed and well trained rofessionals are delivering care in whatever capacity available in order to guarantee atients are recei ing the safest, most e ecti e care he in uence of the current andemic on care deli ery has created opportunity to innovate in order to improve health outcomes; howe er, it will remain ey to e ecti ely manage the increasingly popular telehealth and home infusion trends.

2. Jercich, Kat. “Vast majority of specialists increased use of telehealth tech during COVID-19 pandemic.” Healthcare IT News, Aug. 26, 2020, https://www.healthcareitnews.com/news/vast-majorityspecialists-increased-use-telehealth-tech-during-covid-19pandemic.

3. Henry, T.A. “After COVID-19, $250 billion in care could shift to telehealth.” American Medical Association, June 18, 2020, https:// www.ama-assn.org/practice-management/digital/after-covid-19250-billion-care-could-shift-telehealth.

4. Bestsennyy, Oleg et al. “Telehealth: A quarter-trillion-dollar postCOVID-19 reality?” McKinsey & Company, May 29, 2020, https:// www.mckinsey.com/industries/healthcare-systems-and-services/ our-insights/telehealth-a-quarter-trillion-dollar-post-covid-19reality.

5. “Understanding the hidden costs of COVID-19’s potential impact on US healthcare.” McKinsey & Company, Sept. 4, 2020, https://www. mckinsey.com/industries/healthcare-systems-and-services/ourinsights/understanding-the-hidden-costs-of-covid-19s-potentialimpact-on-us-healthcare.

6. “Update on Home Infusion & Medicare During COVID-19 Pandemic.” GBS/CIDP Foundation International, April 2, 2020, https://www.gbs-cidp.org/update-on-home-infusion-medicareduring-covid-19-pandemic/.

7. Laughlin, Amy et al. “Accelerating the Delivery of Cancer Care at Home During the COVID-19 Pandemic.” NEJM Catalyst, July 7, 2020, https://catalyst.nejm.org/doi/full/10.1056/cat.20.0258.

8. Donlan, Andrew. “Coronavirus Paving the Way for Home Infusion Services Moving Forward.” Home Health Care News, April 21, 2020, https://homehealthcarenews.com/2020/04/coronavirus-pavingthe-way-for-home-infusion-services-moving-forward/.

9. Benefts Cloud Based echnology Brings to Home Infusion During COVID-19.” Option Care Health, Sept. 3, 2020, https:// o tioncarehealth com news enefts cloud ased technology brings-to-home-infusion-during-covid-19.

10. “Impact Analysis of COVID-19 on Home Infusion Therapy Market: Global Opportunity Analysis and Industry Forecast, 2020-2027.” Research Dive, 2020, https://www.researchdive.com/covid-19insights/360/home-infusion-therapy-market#myQueryForm.

11. “CMS Finalizes Calendar Year 2021 Payment and Policy Changes for Home Health Agencies and Calendar Year 2021 Home Infusion hera y Beneft Centers for Medicare & Medicaid Ser ices, Oct 29, 2020, https://www.cms.gov/newsroom/fact-sheets/cmsfnalizes calendar year ayment and olicy changes home health-agencies-and-calendar-year.

12. “Infusion FAQs.” National Home Infusion Association, http://w.nhia. org/faqs.cfm.

1. Koonin, Lisa et al. “Trends in the Use of Telehealth During the Emergence of the COVID-19 Pandemic — United States, January¬–March 2020.” Weekly, Oct. 30, 2020. 69(43);1595-1599. https:// www.cdc.gov/mmwr/volumes/69/wr/mm6943a3.htm. eferences

13. Inserro, Allison. “Home Infusion Services for Part B Drugs in the Spotlight Amid COVID-19 Regulatory Changes.” The American Journal of Managed Care, April 10, 2020, https://www.ajmc.com/ view/home-infusion-services-for-part-b-drugs-in-the-spotlightamid-covid19-regulatory-changes.

14. “Health Insurance Providers Respond to Coronavirus (COVID-19).” America’s Health Insurance Plans, March 10, 2021, https://www. ahip.org/health-insurance-providers-respond-to-coronaviruscovid-19/.

   

  
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BRIEF SUMMARY OF FULL PRESCRIBING INFORMATION

ENTYVIO (vedolizumab) for injection, for intravenous use

FULL PRESCRIBING INFORMATION

INDICATIONS AND USAGE

ENTYVIO is indicated in adults for the treatment of:

ïmoderately to severely active ulcerative colitis.

ïmoderately to severely active Crohnís disease.

CONTRAINDICATIONS

ENTYVIO is contraindicated in patients who have had a known serious or severe hypersensitivity reaction to ENTYVIO or any of its excipients (such as dyspnea, bronchospasm, urticaria, flushing, rash and increased heart rate) [see Warnings and Precautions]

WARNINGS AND PRECAUTIONS

Infusion-Related Reactions and Hypersensitivity Reactions

Infusion-related reactions and hypersensitivity reactions have been reported, including anaphylaxis, dyspnea, bronchospasm, urticaria, flushing, rash, and increased blood pressure and heart rate [see Adverse Reactions]. These reactions may occur with the first or subsequent infusions of ENTYVIO and may vary in their time of onset from during infusion or up to several hours post-infusion.

If anaphylaxis or other serious infusion-related or hypersensitivity reactions occur, discontinue administration of ENTYVIO immediately and initiate appropriate treatment.

Infections

Patients treated with ENTYVIO are at increased risk for developing infections [see Adverse Reactions]. The most commonly reported infections in clinical trials occurring at a rate greater on ENTYVIO than placebo involved the upper respiratory and nasal mucosa (e.g., nasopharyngitis, upper respiratory tract infection). Serious infections have also been reported in patients treated with ENTYVIO, including anal abscess, sepsis (some fatal), tuberculosis, salmonella sepsis, Listeria meningitis, giardiasis and cytomegaloviral colitis. ENTYVIO is not recommended in patients with active, severe infections until the infections are controlled. Consider withholding treatment in patients who develop a severe infection while on treatment with ENTYVIO. Exercise caution when considering the use of ENTYVIO in patients with a history of recurring severe infections. Consider screening for tuberculosis (TB) according to the local practice. For progressive multifocal leukoencephalopathy (PML), see Warnings and Precautions

Progressive Multifocal Leukoencephalopathy

PML, a rare and often fatal opportunistic infection of the central nervous system (CNS), has been reported with systemic immunosuppressants, including another integrin receptor antagonist. PML is caused by the John Cunningham (JC) virus and typically only occurs in patients who are immunocompromised. One case of PML in an ENTYVIO-treated patient with multiple contributory factors has been reported in the postmarketing setting (e.g., human immunodeficiency virus [HIV] infection with a CD4 count of 300 cells/mm3 and prior and concomitant immunosuppression). Although unlikely, a risk of PML cannot be ruled out.

Monitor patients on ENTYVIO for any new onset, or worsening, of neurological signs and symptoms. Typical signs and symptoms associated with PML are diverse, progress over days to weeks, and include progressive weakness on one side of the body or clumsiness of limbs, disturbance of vision, and changes in thinking, memory, and orientation leading to confusion and personality changes. The progression of deficits usually leads to death or severe disability over weeks or months. If PML is suspected, withhold dosing with ENTYVIO and refer to a neurologist; if confirmed, discontinue dosing permanently.

Liver Injury

There have been reports of elevations of transaminase and/or bilirubin in patients receiving ENTYVIO. In general, the combination of transaminase elevations and elevated bilirubin without evidence of obstruction is generally recognized as an important predictor of severe liver injury that may lead to death or the need for a liver transplant in some patients. ENTYVIO should be discontinued in patients with jaundice or other evidence of significant liver injury [see Adverse Reactions]

Live and Oral Vaccines

Prior to initiating treatment with ENTYVIO, all patients should be brought up to date with all immunizations according to current immunization guidelines. Patients receiving ENTYVIO may receive non-live vaccines (e.g., influenza vaccine injection) and may receive live vaccines if the benefits outweigh the risks. There are no data on the secondary transmission of infection by live vaccines in patients receiving ENTYVIO [see Adverse Reactions]

ADVERSE REACTIONS

The following topics are also discussed in detail in the Warnings and Precautions section:

ï Infusion-Related Reactions and Hypersensitivity Reactions [see Warnings and Precautions]

ïInfections [see Warnings and Precautions]

ï Progressive Multifocal Leukoencephalopathy [see Warnings and Precautions]

ïLiver Injury [see Warnings and Precautions]

Clinical Trials Experience

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.

The data described below reflect exposure to ENTYVIO in 3,326 patients and healthy volunteers in clinical trials, including 1,396 exposed for greater than one year, and 835 exposed for greater than two years.

The safety data described in Table 2 are derived from four controlled Phase 3 trials (UC Trials I and II, and CD Trials I and III); data from patients receiving open-label ENTYVIO treatment at Weeks 0 and 2 (prior to entry into UC Trial II and CD Trial III) and from Weeks 6 to 52 (non-responders at Week 6 of UC Trial I and CD Trial I) are included.

In these trials, 1,434 patients received ENTYVIO 300 mg for up to 52 weeks, and 297 patients received placebo for up to 52 weeks. Of these, 769 patients had ulcerative colitis and 962 patients had Crohnís disease. Patients were exposed for a mean duration of 259 days (UC Trials I and II) and 247 days (CD Trials I and III).

Adverse reactions were reported in 52% of patients treated with ENTYVIO and 45% of patients treated with placebo (UC Trials I and II: 49% with ENTYVIO and 37% with placebo; CD Trials I and III: 55% with ENTYVIO and 47% with placebo). Serious adverse reactions were reported in 7% of patients treated with ENTYVIO compared to 4% of patients treated with placebo (UC Trials I and II: 8% with ENTYVIO and 7% with placebo; CD Trials I and III: 12% with ENTYVIO and 9% with placebo).

The most common adverse reactions (reported by 3% of patients treated with ENTYVIO in the UC Trials I and II and CD Trials I and III combined group and 1% higher than in combined placebo group) were nasopharyngitis, headache, arthralgia, nausea, pyrexia, upper respiratory tract infection, fatigue, cough, bronchitis, influenza, back pain, rash, pruritus, sinusitis, oropharyngeal pain and pain in extremities (Table 2)

Table 2. Adverse Reactions in 3% of ENTYVIO-Treated Patients and 1% Higher than in Placebo (UC Trials I and II* and CD Trials I and III*)

Adverse Reaction

*Data from patients receiving open-label ENTYVIO treatment at Weeks 0 and 2 (prior to entry into UC Trial II and CD Trial III) and from Weeks 6 to 52 (non-responders at Week 6 of UC Trial I and CD Trial I) are included.

Ü Patients who received ENTYVIO for up to 52 weeks.

á Patients who received placebo for up to 52 weeks.

Safety data for patients (n=279) in UC Trials I and II and CD Trials I and III who received ENTYVIO at Weeks 0 and 2 and were then randomized to placebo at Week 6 for up to 52 weeks, and for patients (n=416) in CD Trial II, a 10 week Crohnís disease trial, are similar to those listed in Table 2

Infusion-Related Reactions and Hypersensitivity Reactions

Serious infusion-related reactions and hypersensitivity reactions including anaphylaxis have been reported following ENTYVIO administration in clinical trials [see Warnings and Precautions] . In UC Trials I and II and Crohnís Trials I and III, one case of anaphylaxis [one out of 1,434 patients treated with ENTYVIO (0.07%)] was reported by a Crohnís disease patient during the second infusion (symptoms reported were dyspnea, bronchospasm, urticaria, flushing, rash and increased blood pressure and heart rate) and was managed with discontinuation of infusion and treatment with antihistamine and intravenous hydrocortisone.

In UC Trials I and II and CD Trials I and III, 4% of patients treated with ENTYVIO and 3% of patients treated with placebo experienced an infusion-related reaction (IRR). The most frequently observed IRR in the patients treated with ENTYVIO (reported more than twice) were nausea, headache, pruritus, dizziness, fatigue, infusion-related reaction, pyrexia, urticaria and vomiting (each of these adverse reactions occurred in <1% in all patients treated with ENTYVIO) and no individual adverse reaction reported occurred at a rate above 1%. These reactions generally occurred within the first two hours after the infusion and resolved with no treatment or following antihistamine and/or IV hydrocortisone treatment. Less than 1% of patients treated with ENTYVIO had IRRs assessed by the investigator as severe, and IRRs requiring discontinuation of study treatment occurred in <1%.

In clinical trials, for patients with mild IRRs or hypersensitivity reactions, physicians were allowed to pretreat with standard medical treatment (e.g., antihistamine, hydrocortisone and/or acetaminophen) prior to next infusion.

Infections

In UC Trials I and II and CD Trials I and III, the rate of infections was 0.85 per patient-year in the patients treated with ENTYVIO and 0.7 per patient-year in the patients treated with placebo [see Warnings and Precautions]. The infections consisted primarily of nasopharyngitis, upper respiratory tract infection, sinusitis and urinary tract infection. Two percent of patients discontinued ENTYVIO due to infections.

In UC Trials I and II and CD Trials I and III, the rate of serious infections was 0.07 per patient-year in patients treated with ENTYVIO and 0.06 per patient-year in patients treated with placebo. Serious infections were more common in Crohnís disease patients than ulcerative colitis patients, and anal abscesses were the most frequently reported serious adverse reaction in Crohnís disease patients. Over 48 months, there was no increase in the rate of serious infections.

In controlled- and open-label long-term extension trials in adults treated with ENTYVIO, serious infections have been reported, including anal abscess, sepsis (some fatal), tuberculosis, salmonella sepsis, Listeria meningitis, giardiasis and cytomegaloviral colitis.

In UC Trials I and II and CD Trials I and III, sepsis, including bacterial sepsis and septic shock, was reported in four of 1,434 (0.3%) patients treated with ENTYVIO and in two of 297 patients treated with placebo (0.7%). During these trials, two Crohnís disease patients treated with ENTYVIO died due to reported sepsis or septic shock; both patients had significant comorbidities and a complicated hospital course that contributed to the deaths. In an open-label, long-term extension trial, additional cases of sepsis (some fatal), including bacterial sepsis and septic shock, were reported. The rate of sepsis in patients with ulcerative colitis or Crohnís disease receiving ENTYVIO was two per 1,000 patient-years.

In clinical trials, all patients were screened for tuberculosis. One case of latent, pulmonary tuberculosis was diagnosed during the controlled trials with ENTYVIO. Additional cases of pulmonary tuberculosis were diagnosed during the open-label trial. All of these observed cases occurred outside the United States, and none of the patients had extrapulmonary manifestations.

Liver Injury

There have been reports of elevations of transaminase and/or bilirubin in patients receiving ENTYVIO [see Warnings and Precautions]. In UC Trials I and II and CD Trials I and III, three patients reported serious adverse reactions of hepatitis, manifested as elevated transaminases with or without elevated bilirubin and symptoms consistent with hepatitis (e.g., malaise, nausea, vomiting, abdominal pain, anorexia). These adverse reactions occurred following two to five ENTYVIO doses; however, based on case report information it is unclear if the reactions indicated drug-induced or autoimmune etiology. All patients recovered following discontinuation of therapy with some requiring corticosteroid treatment. In controlled trials, the incidence of ALT and AST elevations 3x ULN was 2% in patients treated with ENTYVIO and in patients treated with placebo. In the open-label trial, one additional case of serious hepatitis was observed.

Malignancies

In UC Trials I and II and CD Trials I and III, malignancies (excluding dysplasia and basal cell carcinoma) were reported in six of 1,434 (0.4%) patients treated with ENTYVIO, including colon cancer (n=2), transitional cell carcinoma (n=1),

breast cancer (n=1), carcinoid tumor of the appendix (n=1) and squamous cell carcinoma (n=1). Malignancy was reported in one of 297 (0.3%) patients treated with placebo (squamous cell carcinoma).

Malignancies (excluding dysplasia and basal cell carcinoma) observed during the ongoing open-label long-term extension trial included B-cell lymphoma, breast cancer, colon cancer, malignant hepatic neoplasm, malignant lung neoplasm, malignant melanoma, lung cancer of primary neuroendocrine carcinoma, renal cancer and squamous cell carcinoma. Overall, the number of malignancies in the clinical trials was small; however, long-term exposure was limited.

Live and Oral Vaccines

There are no data on the secondary transmission of infection by live vaccines in patients receiving ENTYVIO.

In a placebo-controlled study of healthy volunteers, 61 subjects were given a single ENTYVIO 750 mg dose (2.5 times the recommended dose), and 62 subjects received placebo followed by intramuscular vaccination with Hepatitis B surface antigen and oral cholera vaccine. After intramuscular vaccination with three doses of recombinant Hepatitis B surface antigen, those treated with ENTYVIO did not have lower rates of protective immunity to Hepatitis B virus. However, those exposed to ENTYVIO did have lower seroconversion rates and anti-cholera titers relative to placebo after receiving the two doses of a killed, oral cholera vaccine. The impact on other oral vaccines and on nasal vaccines in patients is unknown.

Immunogenicity

As with all therapeutic proteins, there is potential for immunogenicity. The detection of antibody formation is highly dependent on the sensitivity and specificity of the assay. Additionally, the observed incidence of antibody (including neutralizing antibody) positivity in an assay may be influenced by several factors, including assay methodology, sample handling, timing of sample collection, concomitant medications, and underlying disease. For these reasons, comparison of the incidence of antibodies to vedolizumab in the studies described below with the incidence of antibodies in other studies or to other products may be misleading.

In UC Trials I and II and CD Trials I and III, in patients who received ENTYVIO, the frequency of antibodies detected in patients was 13% at 24 weeks after the last dose of study drug (greater than five half-lives after last dose). During treatment, 56 of 1,434 (4%) of patients treated with ENTYVIO had detectable anti-vedolizumab antibody at any time during the 52 weeks of continuous treatment. Nine of 56 patients were persistently positive (at two or more study visits) for anti-vedolizumab antibody and 33 of 56 patients developed neutralizing antibodies to vedolizumab. Among eight of these nine subjects with persistently positive anti-vedolizumab antibody and available vedolizumab concentration data, six had undetectable and two had reduced vedolizumab concentrations. None of the nine subjects with persistently positive anti-vedolizumab antibody achieved clinical remission at Weeks 6 or 52 in the controlled trials.

Postmarketing Experience

The following adverse reactions have been identified during post-approval use of ENTYVIO. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

Immune system disorders: Anaphylaxis [see Warnings and Precautions]

DRUG INTERACTIONS

Natalizumab

Because of the potential for increased risk of PML and other infections, avoid the concomitant use of ENTYVIO with natalizumab.

TNF Blockers

Because of the potential for increased risk of infections, avoid the concomitant use of ENTYVIO with TNF blockers.

Live Vaccines

Live vaccines may be administered concurrently with ENTYVIO only if the benefits outweigh the risks [see Warnings and Precautions]

USE

IN SPECIFIC POPULATIONS

Pregnancy

Pregnancy Exposure Registry

There is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to ENTYVIO during pregnancy. Information about the registry can be obtained by calling 1-877-TAKEDA7 (1-877-825-3327).

Risk Summary

Available pharmacovigilance data, data from the ongoing pregnancy registry, and data from published case reports and cohort studies in pregnant women have not identified an ENTYVIO associated risk of major birth defects, miscarriage or adverse maternal or fetal outcomes. There are risks to the mother and the fetus associated with inflammatory bowel disease in pregnancy (see Clinical Considerations) . No fetal harm was observed in

animal reproduction studies with intravenous administration of vedolizumab to rabbits and monkeys at dose levels 20 times the recommended human dosage (see Data)

The estimated background risk of major birth defects and miscarriage for the indicated populations is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2 to 4% and miscarriage is 15 to 20%, respectively.

Clinical Considerations

Disease-associated maternal and embryo/fetal risk

Published data suggest that the risk of adverse pregnancy outcomes in women with inflammatory bowel disease (IBD) is associated with increased disease activity. Adverse pregnancy outcomes include preterm delivery (before 37 weeks of gestation), low birth weight (less than 2,500 g) infants, and small for gestational age at birth.

Fetal/Neonatal adverse reactions

ENTYVIO administered during pregnancy could affect immune responses in the in utero exposed newborn and infant. The clinical significance of low levels of ENTYVIO in utero-exposed infants is unknown. The safety of administering live or live-attenuated vaccines in exposed infants is unknown.

Data

Animal Data

A reproduction study has been performed in pregnant rabbits at single intravenous doses up to 100 mg/kg administered on gestation Day 7 (about 20 times the recommended human dosage) and has revealed no evidence of impaired fertility or harm to the fetus due to vedolizumab. A pre- and post-natal development study in monkeys showed no evidence of any adverse effect on pre- and post-natal development at intravenous doses up to 100 mg/kg (about 20 times the recommended human dosage).

Lactation

Risk Summary

Available published literature suggests the presence of vedolizumab in human milk. The effects of local gastrointestinal exposure and expected low systemic exposure to vedolizumab on the breastfed infant are unknown. There are no data on the effects of vedolizumab on the breastfed infant, or the effects on milk production. The developmental and health benefits of breastfeeding should be considered along with the motherís clinical need for ENTYVIO and any potential adverse effects on the breastfed infant from ENTYVIO or from the underlying maternal condition.

Pediatric Use

Safety and effectiveness of ENTYVIO in pediatric patients have not been established.

Geriatric Use

Clinical trials of ENTYVIO did not include sufficient numbers of subjects aged 65 and over (46 Crohnís and ulcerative colitis patients aged 65 and over were treated with ENTYVIO during controlled Phase 3 trials) to determine whether they respond differently from younger subjects. However, no overall differences in safety or effectiveness were observed between these patients and younger patients, and other reported clinical experience has not identified differences in responses between the elderly and younger patients.

Manufactured by:

Takeda Pharmaceuticals America, Inc. Deerfield, IL 60015

U.S. License No. 1898

Revised: March 2020

ENTYVIO is a trademark of Millennium Pharmaceuticals Inc. and is used under license by Takeda Pharmaceuticals America, Inc.

All other trademark names are the property of their respective owners.

©2014 ñ 2020 Takeda Pharmaceuticals America, Inc.

For more information, go to www.ENTYVIO.com or call 1-877-TAKEDA-7 (1-877-825-3327).

VMB245 R4_Brf04/20

Wet Age-Related Macular Degeneration:

Changing reatment andsca e and Im act

merging thera ies, including iosimilars, will resent new o ortunities and challenges in the management of wAMD

Sneha Sharma, Pharm.D. Clinical Medical

Pharmacy Liaison

Magellan Rx Management

Mihir Patel, Pharm.D. Vice President, Pharmacy Services

PacifcSource

Age-related macular degeneration (AMD) is an eye disease that impacts 11 million Americans and 170 million worldwide.1 S ecifcally, cases of wet AMD wAMD are antici ated to increase to million in the S y wAMD costs the healthcare industry illion annually, and costs are ex ected to increase proportionate to prevalence.

wAMD occurs due to macular damage of the retina and is the leading cause of se ere ision loss in the U.S. , he condition is characterized y new, a normal lood essels growing under the retina, which may lea lood or other uids and result in scarring of the macula wAMD leads to lurriness in ision, which causes a continual loss of central ision, as well as macular changes, when left untreated Risk factors include ha ing a oor diet, eing o erweight, smo ing, eing older than , ha ing high lood ressure, and ha ing a family history of the disease

Current Treatment Considerations for wAMD

wAMD is a chronic disease that, while treata le, is not cura le he goal of treatment is to achie e and maintain a dry macula Current a aila le frst line treatments for wAMD are anti ascular endothelial growth factor V GF in ecta le drugs, including com ounded or reconstituted e acizuma A astin®) which is not FDA a ro ed for use ut acce ted as standard of care, a i erce t A® , rani izuma C N IS® , ega tani Macugen® , and rolucizuma d ll B OV ®).1

he standard of care for atients with wAMD is ty ically e acizuma dosed e ery four wee s , rani izuma dosed e ery four wee s , or a i erce t dosed e ery eight wee s While brolucizumab may e dosed u to e ery wee s, ro ider in ut has indicated this drug is eing used as a last line due to the associated ris of intraocular in ammation com ared to a ris in the other referred drugs. Additionally, ega tani Macugen®) has very little utilization.

Table 1. Cost of Anti-VEGF Therapies

Drug A D Dose and re uency Cost/Dose (ASP+6%) Annual Cost per ye

bevacizumab (Avastin®) mg monthly

a i erce t A®)

mg monthly for frst doses, then mg e ery wee s ,

rani izuma C N IS®) mg monthly ,

pegaptanib (Macugen®) mg e ery wee s ,

Brolucizuma d ll B OV ®) mg monthly for frst doses, then mg e ery wee s ,

o reduce in ection urden in atients with wAMD, two anti V GF treatment a roaches ha e een used treat and extend & and ro re nata P N he & a roach extends the dosing inter al in two wee increments to a maximum of to wee s, and if disease acti ity is o ser ed, the inter al will e reduced accordingly sing the P N a roach, atients must com ly with monthly monitoring, ut in ections are delayed unless recurrent disease acti ity is o ser ed the ey to successful P N a roach is fre uent, consistent monitoring.

ach a aila le thera y has een ro en e ecti e to treat wAMD the di erences etween o tions are regimen and safety rofles Clinical trials, ractice training, and atient status commonly factor into the choice of drug Be acizuma , although o la el for wAMD, is endorsed y the American Academy of O hthalmology AAO and is widely used 7 Howe er, there are some concerns a out com ounding the drug, including inconsistent otency, articulate contamination in syringes, and syringe malfunctions 8 hus, while bevacizumab is a clinically appropriate drug and recommended by the AAO, it is not a reference for many ro iders due to the o label use and the concern regarding compounding.

arly diagnosis and atient education are ey for e ecti e treatment of wAMD reatment duration and access to isits can resent a challenge to some atients, es ecially gi en the intraocular route of administration 9 Patients must e aware of the im ortance of treatment adherence and ersistence adherence concerns may weigh into the thera y decision ma ing rocess for ro iders 9

Treatment Costs

wAMD and associated therapies are a Medicare top 10 spend in drug thera y Centers for Medicare & Medicaid Ser ices CMS data from shows the s end for a i erce t was more than illion, ma ing it the to drug s end in , and this trend

is ex ected to continue 10 From to , the num er of o hthalmic drug in ections increased from , to million.11 In Medicare Ad antage, the o hthalmic in ections a i erce t and rani izuma are the fourth and ffth highest in s end, with increases of and , res ecti ely, since the re ious year According to the Magellan x Management Medical Pharmacy rend e ort, o hthalmic anti V GF in ections were the second highest er mem er er month PMPM Medicare cost for medical eneft drugs in , ehind oncology

he cost for o hthalmic drug thera y ranges from to , er eye annually his cost does not include ofce isits, imaging y o tical coherence tomogra hy to measure disease rogression, trans ortation concerns, or any other associated or indirect costs See a le for a rea down of cost er o hthalmic drug

Biosimilar Pipeline

Se eral iosimilars of o hthalmic drugs are in de elo ment Be acizuma i g NAVA®, Outloo hera eutics is currently in hase three trials and is the frst antici ated launch The initial trial was a superiority trial comparing bevacizumab-vikg to ranibizumab. It demonstrated well tolerated safety with no ocular ad erse e ents related to in ammation, and outcomes re orted were a three-line visual acuity gain. he hase three trial is ongoing, with results ex ected in of Biosimilars for rani izuma uin and Formycon and a i erce t Biogen and Amgen are undergoing phase three trials as well.

Other Emerging Therapies

Abicipar pegol15, 16

Abicipar pegol (Allergan) is a smaller molecule recombinant DARPin

rotein In June , the FDA issued a Com lete es onse etter C in res onse to the iologics license a lication for a ici ar egol he C indicated that the rate of intraocular in ammation o ser ed following the administration of mg ml of a ici ar egol in the hase three studies resulted in an unfa ora le eneft ris in the treatment of wAMD he rate of re orted intraocular inammation was a out Allergan is further studying a ici ar egol in a MAP study with the o ecti e to remo e drug im urities to reduce drug induced in ammation

Faricimab17

Faricima oche has two mechanisms of action, anti V GF and Ang , to hel reduce in ammation due to increased rece tor inding In the hase two S AI A trial, faricima demonstrated clinically meaningful isual acuity gains at a mg dose from aseline to se en letters and uid reductions at wee s dosing, com ared to rani izuma e ery four wee s he trial included treatment na e atients two atients recei ing faricima re orted intraocular in ammation As the atient o ulation for trials increases, the rate of this ad erse e ent may e im acted

Ranibizumab Port Delivery System18

The ranibizumab port delivery system is under phase three and extension studies within A CH A , com aring the im lant to rani izuma he ort is the size of a grain of rice, ut it re uires surgery. The previous study ladder was done with treatmentex erienced atients In hase two of the study, atients showed to e dose de endent, with the high concentration dosing arm having the best outcomes in visual acuity. The high-dose arm had similar results to rani izuma administered ia IV and was well tolerated, with in ammation esults were similar in safety and

efcacy to mg of rani izuma ani izuma in ANCHO and MA INA studies had less than in ammation rates he ort would re uire refll e ery six months

Potential Impact and Payer Considerations

Des ite the su stantial atient urden of wAMD, a re orted to of Medicare atients treated with anti V GF discontinue treatment.19 Hesitance a out in ections and lac of atient education can lead to the discontinuation of anti V GF treatment howe er, cost is often a ma or factor in this decision As the anti V GF treatment becomes increasingly competitive with the development and imminence of iosimilars for a i erce t and rani izuma , the urden of cost on atients may ecome more managea le

Medicare mem er coinsurance could ary for the iosimilar due to lac of ricing standardization he rice will determine Medicare atients coinsurance, which could otentially result in Medicare atients ha ing higher out of oc et s end for iosimilars than commercially insured atients As in any s ecialty s ace, there are atient assistance rograms set u , such as Health ell, CDF, and PANF, that may hel atients with out of oc et ex enses Howe er, ricing for iosimilars will need to e monitored, and formulary management strategies should e used to hel alle iate any disparities.

Management strategies should be developed using historical utilization patterns and step therapy programs should be considered, along with recommendations from ey o inion leaders and ro ider focused education regarding wAMD and the roader o hthalmology mar et As the re alence of wAMD increases, more drugs in the pipeline will create a more competitive landscape where biosimilar drugs and pricing strategies will help to lower costs.

Drug Company Mechanism of Action oute of DosageStatus

Table 2. wAMD Biosimilar Pipeline14

1. “Age-Related Macular Degeneration (AMD) Data and Statistics.” National Institute of Health, July , , htt s www nei nih go learn a out eye health resources for health educators eye health data and statistics age related macular degeneration amd data and-statistics.

Pennington, atie and Margaret DeAngelis idemiology of age-related macular degeneration (AMD): associations with cardio ascular disease henoty es and li id factors ye and Vision, , htt s www nc i nlm nih go mc articles PMC

Boyd, ierstan hat Is Macular Degeneration American Academy of O hthalmology, Jan , , htt s www aao org eye health diseases amd macular degeneration

homas, Michael et al Com arati e e ecti eness of a i erce t for the treatment of atients with neo ascular age related macular degeneration Clinical O hthalmology, Mar , , htt s www nc i nlm nih go mc articles PMC

Mon s, Jordi et al is of In ammation, etinal Vasculitis, and etinal Occlusion elated ents with Brolucizuma Post Hoc e iew of HA and HA I American Academy of O hthalmology, No , , htt s www aao ournal org article S fulltext

Baumal, Caroline et Age elated Macular Degeneration reatment Ad ances to educe the In ection Burden AJMC, May , , htt s www a mc com iew wet agerelated macular degeneration treatment ad ances to reduce the in ection urden

7. Ge er, John AAO Be acizuma o s Anti V GF Choice in AMD MedPage oday, Oct , , htt s www med agetoday org meetingco erage aao ass

8. VanderBee , Brian et al he association etween com ounding e acizuma and ost in ection endo hthalmitis JAMA O hthalmolog, Oct , , htt s www nc i nlm nih go mc articles PMC

9. Gerson, Je ry How arly Diagnosis Can Im ro e AMD Outcomes e iew of O tometry, Se t , , htt s www re iewofo tometry com article how early diagnosis can im ro e amd-outcomes.

10. Medicare Part B Drug S ending Dash oard Centers for Medicare & Medicaid Ser ices, Oct , www cms go esearch Statistics Data and Systems Statistics rends and e orts Information on Prescri tion Drugs MedicarePartB

11. Gins urg, Paul and George illiams reatment S ecifc Payment A roaches he Case of Macular Degeneration HealthA airs, No , , htt s www healtha airs org do h log full

Medical Pharmacy rend e ort Magellan x Management, , htt s www magellanrx com documents mrx medical harmacy trend re ort df

Outloo hera eutics Doses First Patient in the Second Phase Clinical rial for ONS in et AMD Outloo hera eutics, July , , htt s www glo enewswire com news release en outloo thera eutics doses frst atient in the second hase clinical trial for ons in wet-amd.html

IPD Analytics htt i danalytics com

Allergan, an A Vie Com any, and Molecular Partners ecei e Com lete es onse etter from FDA on Biologics icense A lication for A ici ar egol A Vie, June , , htt s news a ie com news ress releases allergan an a ie company-and-molecular-partners-receive-complete-responseletter from fda on iologics license a lication for a ici ar egol htm.

unimoto, Dere et al fcacy and Safety of A ici ar in Neo ascular Age elated Macular Degeneration O hthalmology, Oct , htt s u med nc i nlm nih go

17. hanani, A et al fcacy of ery Four Monthly and uarterly Dosing of Faricima s ani izuma in Neo ascular Age elated Macular Degeneration he S AI A Phase andomized Clinical rial JAMA O hthalmology, , htt s www semanticscholar org a er fcacy of ery Four Monthly and uarterly Dosing hanani Patel d e ecfc cd dce fddc cf

18. Phase III data shows oche s Port Deli ery System with rani izuma ena led o er of atients to go six months etween treatments for neo ascular age related macular degeneration oche, July , , htt s www glo enewswire com news release en Phase III data show-Roche-s-Port-Delivery-System-with-ranibizumab-enabledo er of atients to go six months etween treatments for neovascular-age-related-macular-degeneration.html.

19. Mulligan, aren et al conomic Value of Anti Vascular ndothelial Growth Factor reatment for Patients with et Age elated Macular Degeneration in the nited States JAMA O hthalmology, Jan , htt s www nc i nlm nih go mc articles PMC text A roximately to of,treatment within the frst year &text Although cost is cited as,theraies is a aila le o Dla el

Mental Health Update:

Digital hera eutics, Drug Pi eline, and COVID-19 Impact

The mental health space has seen many advances in the development of digital therapies and robust i elines across many indications, as well as challenges rought on y the COVID andemic

Stacy Inman, Pharm.D. Senior Clinical Project Manager

Magellan Method

The public health crisis throughout the past year has made the importance of mental health management more a arent than e er ith an e er ex anding digital thera eutics o ering and i eline, treatment innovations for an array of mental health conditions are on the horizon.1 The mental health space is also ex eriencing road i elines for de ression, schizo hrenia, and i olar disorder As an increasing number of individuals are reporting a negative impact on their mental health due to the COVID-19 pandemic, treatment and inter entions will e rioritized in the coming years as the world reco ers from the pandemic and its long-lasting implications. ,

Digital Therapeutics in Mental Health

Digital thera eutics, defned y the Digital hera eutics Alliance as e idence ased thera eutic inter entions dri en y high uality software rograms to re ent, manage, or treat a medical disorde or disease, are changing the landsca e of mental health management and increasing access to care Generally, these thera eutics ena le thera y y ex anding the role of human su ort S ecifc ally, digital thera eutics ha e emerged as a new method of re enting, managing, or treating chronic, eha ior modifa le disease Digital thera eutics are currently in de elo ment for a wide range of mental health or eha ioral health conditions, including su stance use disorder, o ioid use disorder, chronic insomnia, schizo hrenia, attention defcit hy eracti ity disorder, autism s ectrum disorder, ma or de ressi e disorder, ost traumatic stress disorder, generalized anxiety, and more See a le for some therapies currently in the digital therapeutics pipeline.

he utility of digital thera eutics has ecome more a arent with the ongoing COVID andemic In light of this, the Food and Drug Administration FDA issued fnal guidance on the enforcement olicy for digital health de ices for the treatment of sychiatric disorders during COVID in A ril 4 The guidance intended to expand availability to digital health devices and applied to computerized eha ioral thera y de ices and other health de ices for sychiatric disorders, as well as low ris wellness and digital health products for mental health or psychiatric conditions.4 The guidance made clear

that the olicy is intended to remain in e ect for the duration of the COVID u lic health emergency howe er, atient and roider reference for these modalities may increase with more access and use.4

Therapy Pipeline

Despite a diverse array of available therapies for mental health conditions, clinicians still loo to no el agents in ho es of improved outcomes.5 The current psychiatric pipeline is robust across de ression, schizo hrenia, and i olar disorder and shows otential inno ati e treatments he i eline romises new thera ies that draw u on esta lished mechanisms of action, as well as thera eutic ad ances to otentially ro ide ho e for e ecti e treatment to atients with su o timal outcomes 5 The pipeline across these mental health conditions can be found in Tables 2-4.

Table 1. Digital Therapeutics Pipeline3

SAG zuranolone Sage hera euticsGABA Modulators MDD PPD phase three

A S u ro ion dextromethor han Axsome hera eutics NDRI MDD phase three d Methadone Relmada Therapeutics NMDA rece tor antagonist MDD phase three ansofaxine hydrochloride uye Pharma NDRI MDD January

MIN seltorexant Minerva Neurosciences; Janssen Orexin receptor antagonistMDD phase three

Cyclurad D cycloserine lurasidone NeuroRx atypical antipsychotic; NMDA rece tor agonist depressive episodes in bipolar I disorder phase three

V A A cari razine hydrochloride Allergan A Vie atypical antipsychoticMDD phase three

MIN rolu eridone

Minerva Neurosciences; Mitsubishi Tanabe H A serotonin rece tor antagonist schizophrenia phase three

S P Suno ion Pharmaceuticals H A serotonin receptor agonist schizophrenia phase three

Nu lazid ima anserin tartrate Acadia Pharmaceuticals atypical antipsychoticschizophrenia phase three

PP M ali eridone almitate Janssen atypical antipsychoticschizophrenia ending Se tem er is eridone ISM o i Pharmaceuticals atypical antipsychoticschizophrenia ending

V ris eridone e a Pharmaceuticals MedinCell atypical antipsychoticschizophrenia phase three

ar xanomeline and tros ium aruna hera euticsM A schizophrenia phase three

Cyclurad D cycloserine lurasidone NeuroRx atypical antipsychotic; NMDA rece tor agonist bipolar disorderphase three

CAP A lumate erone tosylate

Intra-Cellular hera ies Bristol Myers S ui atypical antipsychotic bipolar disorder phase three

B C dexmedetomidine hydrochloride Bio cel hera eutics selective alpha2adrenoreceptor agonist sedative bipolar disorderphase three

V A A cari razine hydrochloride Allergan A Vie atypical antipsychoticbipolar disorderphase three ndoxifen

Jina Pharmaceuticals Intas Pharmaceuticals selective estrogen receptor modulator bipolar disorderphase three

G ODON zi rasidone hydrochloride Pfzer atypical antipsychoticbipolar disorder phase three

I rex i razole H und ec A S Otsu a atypical antipsychoticbipolar disorderphase three

Table 2. Depression Pipeline6

Table 3. Schizophrenia Pipeline6

Table 4. Bipolar Disorder Pipeline6

53% of adults in the U.S. reported that stress and worry due to the pandemic have negatively impacted their mental health, compared to 32% in March 2020.

Impact of COVID-19

According to a July aiser Family Foundation oll, of adults in the S re orted that stress and worry due to the andemic ha e negati ely im acted their mental health, com ared to in March As the andemic and resulting economic, social, and hysical im lications continue, mental health challenges will ersist and new arriers will arise for those who already su ered from mental illness or su stance use disorders Another re ort from the S Centers for Disease Control and Pre ention noted that anxiety symptoms tripled and depression symptoms uadru led among adults sur eyed when com ared to a survey; two additional studies from A ril re orted that deressi e sym toms and serious sychological distress were three times that measured in , Across studies and re orts, those most a ected were those with reexisting mental health issues, low income indi iduals, eo le of color, those close to someone who su ered or died from COVID , those with Asian ethnicity, and young adults ages to , , Income insecurity, o loss, grief, fear of illness, and social isolation are all elie ed to contribute to the negative mental health impact on society.

hile this im act is closely tied to the andemic, the im lications for mental health are li ely to e long term, articularly for those at ris for new or exacer ated mental health challenges It is currently unclear the extent to which the num er of those reorting negati e mental health sym toms will increase howe er, if the current trend continues, the o erall im act will li ely ha e a su stantial im act on healthcare Both those who li ed with mental illness or substance-use disorders prior to the pandemic and those who are newly a icted from the andemic will li ely re uire mental healthcare and management in a ost andemic world, heightening the need for treatment options and access to care for an expanded patient population.

Managed Care Implications

Mo ing forward, there will li ely e a long term shift in oth the management of mental health and the needs in this space. The promising drug pipeline across mental health indications coupled with the increased utilization and access to digital thera eutics will face ayers with oth o ortunities for etter outcomes as well as a need for e ecti e management Additionally, the roadening o ulation of those who will eneft from mental health treatment and solutions will increase the im ortance of rioritizing strategic solutions and management in this space.

References

1. Patel, Nisarg and Atul Butte Characteristics and challenges of the clinical i eline of digital thera eutics Nature, Dec , , htt s www nature com articles s

2. Pan, uan u et al he mental health im act of the COVID andemic on eo le with and without de ressi e, anxiety, or obsessive-compulsive disorders: a longitudinal study of three Dutch case control cohorts he ancet Psychiatry, Fe , , htt s www thelancet com ournals lan sy article PIIS fulltext

Panchal, Nirmita et al he Im lications of COVID for Mental Health and Su stance se aiser Family Foundation, Aug , , htt s www org corona irus co id issue rief the im lications of co id for mental health and su stance use

4. nforcement Policy for Digital Health De ices for reating Psychiatric Disorders During the Corona irus Disease COVID Pu lic Health mergency Guidance for Industry and Food and Drug Administration Sta S Food & Drug Administration, A ril , htt s www fda go regulatory information search fda guidance documents enforcement olicy digital-health-devices-treating-psychiatric-disorders-duringcoronavirus-disease.

5. Miller, John he Psychiatric Pi eline Agents to atch Psychiatric imes, Jan , , htt s www sychiatrictimes com iew sychiatric i eline agents watch

IPD Analytics, htt s i danalytics com

Czeisler, Mar et al Mental Health, Su stance se, and Suicidal Ideation During the COVID Pandemic nited States, June , S Centers for Disease Control and Pre ention, ee ly, Aug , , htt s www cdc go mmwr olumes wr mm a htm

ttman, Catherine et al Pre alence of De ression Sym toms in S Adults Before and During the COVID Pandemic JAMA Netw O en, Se t , , htt s amanetwor com ournals amanetwor o en fullarticle

9. McGinty, mma et al Psychological Distress and oneliness e orted y S Adults in and A ril JAMA, June , , htt s amanetwor com ournals ama fullarticle

AT MAGELLAN METHOD, we are uniquely qualified to solve complex healthcare challenges. As a subsidiary of Magellan Health, a Fortune 500 company, we have access to a wide range of resources and expertise from across our PBM, Medicare, and behavioral health divisions.

We leverage up-to-date healthcare data to implement solutions that transform how care is delivered. Our team of analytic experts partners with you to develop a customized solution that delivers results.

How can we put our Method to work for you? Contact us at MagellanMethod@magellanhealth.com to learn

Multiple Myeloma:

reatment date, CA , and Im act

merging thera ies for multi le myeloma, es ecially CA , could resent exciting o ortunities for im ro ed outcomes howe er, ayers will face challenges managing the associated high costs

Michele Bautista Meredith, Pharm.D.

Director, Pharmacy Services

Sharp Community Medical Group

Multi le myeloma is a rare cancer that a ects lasma cells found in the one marrow, where lood cells are made , Plasma cells ma e anti odies that lay a ey role in hel ing the immune system fght o infection In atients with multi le myeloma, their once normal lasma cells mutate into cancerous cells that grow out of control and roduce an a normal anti ody called M rotein 2 As the cancerous cells continue to multi ly, they lea e little room for normal lasma cells his causes a decrease in red lood cells, white lood cells, and latelets, which otentially leads to anemia, excessi e leeding, and decreased a ility to fght o infection , Furthermore, atients with multi le myeloma may ex erience one damage, hy ercalcemia, and idney damage ,

In the S , an estimated , eo le will e diagnosed with multi le myeloma, and it will cause a out , deaths annually Many drug thera ies that treat multi le myeloma are used in com ina tion and therefore dri e the cost u astronomically high, with a range of , to , er treatment 4 ith no cure to this cancer, the goal is to ro ide atients with sym tom management and hel them maintain cancer remission

Current State of Treatment and Guidelines

For multi le myeloma, current treatments to hel control sym toms and slow down disease rogres sion include immunomodulators lenalidomide, omalidomide, thalidomide , roteasome inhi itors ortezomi , carflzomi , or ixazomi , corticosteroids, monoclonal anti odies, chemothera y, and for eligi le atients, hemato oietic stem cell trans lant HSC 5

For acti e multi le myeloma, it is recommended to use tri let thera y to achie e the est res onse Hemato oietic stem cell trans lant is usually suggested for atients under the age of Howe er, it is im ortant to consider not only age ut also the atient s hysical health, as high dose chemothera y is re uired efore recei ing a hemato oietic stem cell trans lant

Current treatments include immunomodulators, proteasome inhibitors, corticosteroids, monoclonal antibodies, chemotherapy, and, for eligible patients, hematopoietic stem cell transplant.

Stay

National Com rehensi e Cancer Networ NCCN Preferred Drug hera ies for Acti e Sym tomatic Multi le Myeloma 5

Stem Cell Transplant-Eligible

• ortezomi lenalidomide dexamethasone

• ortezomi cyclo hos hamide dexamethasone

Non-Stem Cell Transplant-Eligible

• ortezomi lenalidomide dexamethasone

• ortezomi cyclo hos hamide dexamethasone

• lenalidomide low dose dexamethasone

• daratumuma ortezomi mel halan rednisone

Along with rimary treatment, ad uncti e thera y is used to im ro e safety, side e ects, or e ecti eness of the rimary treat ment 5 hese ad uncti e thera ies are s ecifc to each atient ased on the sym toms and side e ects they ex erience with their treatment therapy:5

• Bis hos honates amidronate or zoledronate or denosuma for one health

• Drug treatment for high calcium le els

• Plasma heresis for hy er iscosity

• rythro oietin for anemia

• Vaccines and treatments for infection

• Blood thinners to re ent lood clots

• Drugs, radiation thera y, or surgery for one ain

• i uids and ossi le lasma heresis to re erse idney damage

Newly Approved Therapies

Selinexor (XPOVIO®)

Selinexor POVIO® , manufactured y aryo harm hera eutics, is an oral selecti e inhi itor of nuclear ex ort SIN that is used in com ination with dexamethasone for atients with refractory disease 7 It wor s y inding and inhi iting the nuclear ex ort rotein, PO , causing the accumulation of tumor su ressor ro teins in the cell nucleus 7 his results in increasing the cells tumor su ressor functions, which leads to selecti e a o tosis in cancer cells all while s aring the normal cells 7

he i otal clinical study of selinexor, S O M, was erformed as a multicenter, single arm, o en la el study Selinexor was e aluated in atients with rela sed or refractory multi le myeloma who had re iously recei ed three or more anti myeloma treatments, in cluding an al ylating agent, glucocorticoids, ortezomi , carflzomi , lenalidomide, omalidomide, and an anti CD monoclonal anti ody 7 he atients recei ed mg of selinexor in com ination with mg of dexamethasone, gi en on days one and three of each wee 7 he a ro al, efcacy, and safety of selinexor was ased on the o erall res onse rate from a res ecifed su grou analysis of atients 7 reatment continued until the disease rogressed or toxicity reached an unacce ta le le el 7 he o erall res onse rate was 7 he median time to frst res onse was four wee s, and the median duration of the res onse was months 7

MULTIPLE MYELOMA

CAR-T therapies are being investigated in clinical trials for patients with relapsed or refractory multiple myeloma and are showing positive results. This therapy functions by activating an individual’s immune system to fght against the cancer.

In Decem er , selinexor was a ro ed y the FDA for a new indication, in com ination with ortezomi and dexamethasone for the treatment of adult atients with multi le myeloma who ha e recei ed at least one rior thera y

Isatuximab-irfc (SARCLISA®)

Isatuxima irfc SA C ISA® , manufactured y Sanof, is an IgG deri ed monoclonal anti ody that inds to CD and is ex ressed on the malignant multi le myeloma cells 9 Isatuxima irfc causes a o tosis of tumor cells and acti ation of immune e ector mechanisms, including anti ody de endent, cell mediated cytotoxicity ADCC anti ody de endent, cellular hagocytosis ADCP and com lement de endent cytotoxicity CDC 9 Isatuxima irfc also inhi its ADP ri osyl cyclase acti i ty of CD , acti ates natural iller cells, and su resses CD ositi e regulatory cells 9

he efcacy and safety of Isatuxima irfc was measured in com ination with omalidomide and low dose dexamethasone, com ared to atients recei ing omalidomide and low dose dexamethasone alone 9 A hase three i otal clinical trial, ICA IA MM, was a multicenter, multinational, randomized, o en la el, two arm study that e aluated atients with rela sed and re fractory multi le myeloma who had recei ed at least two re ious thera ies, including lenalidomide and a roteasome inhi itor 9 he atients were randomized in a ratio to recei e mg g of isatuxima irfc ia IV infusion wee ly for the frst cycle, then e ery two wee s thereafter in com ination with mg of omalidomide ta en orally on days one to each cycle and mg of dexamethasone

mg for atients o er gi en on days one, eight, , and 9 his three drug com ination was gi en in day cycles un til the disease rogressed or toxicity reached an unacce ta le le el 9 Isatuxima irfc s rimary efcacy end oint was rogres sion free sur i al PFS , which is the amount of time the atient stays ali e without their cancer rogressing 9 he isatuxima irfc, omalidomide, and dexamethasone grou had a res onse rate of and showed im ro ement in PFS with a ris re duction of disease rogression or death 9 Patients who recei ed omalidomide and low dose dexamethasone alone had a res onse rate of 9 he median duration of treatment was wee s for the isatuxima irfc, omalidomide, and dexamethasone grou , and wee s for the omalidomide and dexamethasone grou 9

Belantamab mafodotin-blmf (BLENREP®)

Belantama mafodotin lmf B N P® , manufactured y GlaxoSmith line, is an anti ody drug con ugate ADC that inds to BCMA a rotein that is ex ressed on multi le myeloma cells and normal B lym hocytes and that releases monomethyl auristatin F MMAF y roteolytic clea age 9 he released MMAF, a microtu ule inhi itor, disru ts the microtu ule networ and results in cell cycle arrest and a o tosis 10

he efcacy of elantama mafodotin lmf was studied in D AMM , an o en la el, multicenter study in atients with re fractory multi le myeloma who had recei ed three or more re ious thera ies 10 Patients recei ed mg g or mg g of elantama mafodotin lmf ia IV once e ery three wee s until the disease rogressed or toxicity reached an unacce ta le le el 10 fcacy was measured y the o erall res onse rate 10 he results only re ected the atients who recei ed the FDA a ro ed recommended dose of mg g of elantama mafodotin lmf 10 he o erall res onse rate was CI , 10 he median time to the frst res onse was months, and of res onders had res onse durations of more than six months 10 Belantama mafodotin lmf has a lac ox warning of otential changes in the corneal e ithelium that can result in ision alter ations, including se ere ision loss, a corneal ulcer, and sym toms such as lurred ision and dry eyes 10 Belantama mafodotin lmf is only a aila le through a restricted rogram under the FDA s is aluation and Mitigation Strategy MS , called the B N P MS, due to the ocular toxicity ris s 10

CAR-T Therapies

Chimeric antigen rece tor cell CA thera y is a new treatment o tion that has demonstrated greatly im ro ed remission rates in lood cancers such as B cell acute lym ho lastic leu emia and

B cell non Hodg in lym homa 11 CA thera ies are eing in estigated in clinical trials for atients with rela sed or refractory multi le myeloma and are showing ositi e results 11 CA thera y functions y acti ating an indi idual s immune system to fght against the cancer 11 his is achie ed y remo ing the atient s cells, genetically engineering them to roduce a surface le el rotein rece tor with the a ility to recognize and attac malignant cells, and then re infusing the cells ac into the atient 11 he most common target rotein for CA thera y in multi le myeloma cells is B cell maturation antigen BCMA 11

Pipeline

Melfufen

Mel ufen is a e tide drug con ugate that wor s y entering a cell to e ro en down y amino e tidases, which releases al ylating agents and ills cells 12 Amino e tidases are roduced in exces si e amounts in cancer cells, thus ecoming the s ecifc target 12 Mel ufen is currently in a hase three clinical study, OC AN OP , and is eing com ared directly against the current standard of care in atients with rela sed or refractory multi le myeloma 12

Idecabtagene vicleucel (ide-cel) is a CAR-T cell therapy that recognizes and binds to BCMA on the surface of multiple myeloma cells — leading to CAR-T cell proliferation, cytokine secretion, and cytolytic killing of BCMA-expressing cells.

In the i otal hase two clinical trial HO I ON OP , mel ufen was used in com ination with dexamethasone in atients with rela sed or refractory multi le myeloma he o erall res onse rate was In atients with tri le class re fractory, the o erall res onse rate was

Idecabtagene vicleucel

Ideca tagene icleucel ide cel is a CA thera y that recog nizes and inds to BCMA on the surface of multi le myeloma cells leading to CA cell roliferation, cyto ine secretion, and cytolytic illing of BCMA ex ressing cells 14

he i otal hase two arMMa trial was an o en la el, sin gle arm, multicenter, multinational study that e aluated the safety and efcacy of ideca tagene icleucel in atients with refractory or rela sed multi le myeloma who had re i ously recei ed at least three treatments, including treatment with an immunomodulatory agent, roteasome inhi itor PI , and a CD directed anti ody 15 Additionally, of atients recei ed re ious autologous HSC , and recei ed ridging thera y rior to lym hode leting chemothera y udara ine and cyclo hos hamide 15 he rimary end oint was the o erall res onse rate, which was Median rogression free sur i al was months 15 Ideca tagene icleucel has a set FDA a ro al date of March If a ro ed, it will e the frst CA thera y indicated for multi le myeloma

The new investigational CAR-T therapies could be groundbreaking for the patients with relapsed or refractory multiple myeloma.

JNJ-4528

JNJ is a CA thera y made of modifed cells that identify and eliminate cancer cells containing BCMA he JNJ hase three trial is currently ongoing he re ious results of the hase one two trial, CA I D , showed an o erall res onse rate of of atients reached a stringent com lete res onse at months and were ali e and rogression free at nine months

Impact of CAR-T and Other Managed Care Implications

he f e year sur i al rate for multi le myeloma is Many atients do not e ecti ely res ond to multi le myeloma thera ies, or they rela se after recei ing treatment he new in estigational CA thera ies could e ground rea ing for the atients with rela sed or refractory multi le myeloma CA thera y is attracti e in that it is a one time dose, though the intensity of the thera y is not to e ta en lightly he huge fnancial urden of CA thera ies is an im ortant consider ation for oth atients and ayers Managed care ayers will also need to ta e into account certain criteria for eligi ility in order to ro ide access to these medications while ee ing cost e ecti eness in mind CA thera y such as ideca ta gene icleucel, if a ro ed, is ro ected at an annual cost of , er atient hile this thera y is not a cure to mul ti le myeloma, it could ha e a large im act for atients who ha e few or no other treatment o tions

References

hat Is Multi le Myeloma American Cancer Society, , htt s www cancer org cancer multi le myeloma a out what is multi le myeloma html

nderstanding multi le myeloma Multi le Myeloma esearch Foundation, htt s themmrf org multi le myeloma

Multi le Myeloma Statistics Cancer Net, May , htt s www cancer net cancer ty es multi le myeloma statistics text Multi le myeloma is not a, e diagnosed with multi le myeloma

Can e A ord the Cost of Myeloma hera y Medsca e, June , , htt s www medsca e com iewarticle

Multi le Myeloma National Com rehensi e Cancer Networ , , htt s www nccn org atients guidelines content PDF myeloma atient df

ole of rans lant International Myeloma Foundation, htt s www myeloma org autologous stem cell trans lant text Autologous stem cell trans lant can,high Ddose chemothera y with mel halan

POVIO® selinexor Newton, MA aryo harm hera eutics

July , htt s www accessdata fda go drugsatfda docs la el s l l df

FDA a ro es selinexor for refractory or rela sed multi le myeloma S Food and Drug Administration, , htt s www fda go drugs drug a ro als and data ases fda a ro es selinexor refractory or rela sed multi le myeloma text On Decem er C C the,at least one rior thera y

SA C ISA® isatuxima irfc Bridgewater, NJ Sanof A entis March , htt s www accessdata fda go drugsatfda docs la el s l l df

BLENREP® elantama mafodotin lmf riangle Par , NC GlaxoSmith line August , htt s www accessdata fda go drugsatfda docs la el s l l df

Bryson, Ste e New CA cell hera y Shows arly Promise Against Multi le Myeloma in a Study Myeloma esearch News, Fe , , htt s myelomaresearchnews com car tcell immunothera y shows romise against rela sed multi le myeloma early la study

A out mel ufen INN mel halan ufenamide Onco e tides, htt s onco e tides se en mel ufen text Mel ufen INN mel halan ufenamide is,al ylating agents into tumor cells

Slater, Hannah FDA Grants Priority e iew to Mel ufen in Com ination with Dexamethasone for Myeloma Cancer Networ , Aug , , htt s www cancernetwor com iew fda grants riority re iew to mel ufen in com ination with dexamethasone for myeloma

Ideca tagene icleucel FDA A ro al Status Drugs com, htt s www drugs com history ideca tagene icleucel html

Slater, Hannah FDA Grants Priority e iew to Ideca tagene Vicleucel for Multi le Myeloma Cancer Networ , Se t , , htt s www cancernetwor com iew fda grants riority re iew to ideca tagene icleucel for multi le myeloma

Janssen s BCMA CA hera y JNJ Showed arly, Dee and Dura le es onses in Hea ily Pretreated Patients with Multi le Myeloma Johnson & Johnson, May , , htt s www n com anssens cma car t thera y n showed early dee and dura le res onses in hea ily retreated atients with multi le myeloma

are Neuromuscular Diseases

reatment and Management Strategies

ith a num er of romising thera ies in the i elines across rare neuromuscular diseases, there will e added challenges for ayers in managing high cost thera ies

Ben Barner, Pharm.D., MBA Senior Director Pharmacy

Fallon Health

are diseases are defned as conditions a ecting fewer than , indi iduals in the nited States

A total cost of illness estimate for certain rare neuromuscular diseases in the S ranges from to illion er year 1 hese costs are ex ected to increase as additional no el agents for certain rare diseases enter the mar et Currently, the drug i eline for rare neuromuscular disorders, such as Duchenne muscular dystro hy DMD , amyotro hic lateral sclerosis A S and other s inal muscular atro hies SMA , and Huntington s disease HD , illustrates an ex anding treatment landsca e 2 he treatment o tions across these disease states ha e historically een limited, and the current i eline is romising Howe er, with no el and inno ati e thera ies come ayer management challenges, s ecif cally around high cost thera ies

Current Treatment Landscape

DMD

DMD treatment ty ically includes generic corticosteroids and MF A A® de azacort to hel main tain strength and slow disease rogression Additionally, angiotensin con erting enzyme AC inhi itors and eta loc ers are used for atients with cardiac damage for their disease 4 OND S ete lirsen and V OND S golodirsen were a ro ed y the Food and Drug Administration FDA for atients with s ecifc mutations of the dystro hin gene in and In , the FDA a ro ed VI PSO® iltolarsen for the same indication , Most recently, in Fe ruary, Amondys casimersen was a ro ed y the FDA

ALS

A S treatment aims to hel control sym toms, re ent com lications, and im ro e uality of life here are currently only two FDA a ro ed drugs indicated for the treatment of A S ilute ® riluzole and ADICAVA® edara one hile riluzole is used widely for atients with all stag es of A S disease rogression, edara one is used fre uently in recently diagnosed atients

rior to signifcant disease rogression A S is also of ten treated with a com rehensi e care management team who ro ide su orti e care, including hysicians har macists hysical, occu ational, and or s eech thera ists nutritionists social wor ers res iratory thera ists clinical sychologists and home care and hos ice nurses he col la orati e team can de elo and ro ide an indi idualized treatment lan, ro ide s ecial e ui ment, and im ro e uality of life

SMA

ntil recently, SMA treatments were restricted to su orti e thera ies howe er, since , treatment of the condition has ex anded with three FDA a ro als for all SMA ty es , he FDA a ro ed SPIN A A® nusinersen in , O G NSMA® onasemnogene a e ar o ec xioi in , and rysdi risdi lam in ,

HD

As with the re iously discussed disorders, there is no cure for HD, and treatment goals focus on managing sym toms, s e cifcally around muscle issues such as contractions, dif culty with oluntary mo ements, and er y in oluntary mo e ments, or chorea 12 In , the FDA a ro ed enazine® tetra enazine as the frst drug s ecifcally indicated for HD tetra enazine is intended to hel su ress chorea ut is of ten associated with worsening de ression and other serious side e ects ater, in , the FDA a ro ed the frst al ternati es to tetra enazine, A S DO® deutetra enazine and ING A® al enazine tosylate , for the treatment of chorea associated with HD , Other treatments for HD sym toms include anti sychotic medications to manage HD associated sychiatric sym toms, li e agitation and sychosis 12

Pipelines

Across these rare disease states, imminent i elines romise inno ati e thera ies that can change the treatment of these disorders Since the current thera y o tions for these rare neuromuscular dis eases are fairly limited, new o tions may resent an o ortunity to im ro e atient outcomes and uality of life See a les for a rea down of treatments in the i eline for DMD, A S, SMA, and HD

Payer Impact and Management

hile the ex ansion of treatment o tions in this s ace creates

an exciting o ortunity for im ro ed atient outcomes, the high cost of these thera ies remains a urden for oth atients and ayers ith a ro ust i eline, there will e increased rioritiza tion around ro er management of these thera ies and atient o ulations Sales associated with rare disease treatment are estimated to increase y annually through , reaching illion In res onse to the high cost thera ies already on the mar et for these rare neuromuscular diseases, ayers ha e underta en eneft design changes to manage oth use and cost associated with treatment, including formulary restriction and s ecialty tiers, shifting from co ayments to co insurance, and rior authorization

In a sur ey of consultants, health lans, and harmacy en eft managers, when as ed to identify the est a roach to man aging the high cost associated with rare diseases, called for a more integrated a roach y eneft managers around total cost of care across the healthcare continuum An additional called for limitations from institutions li e the National Institute of Health and Care xcellence or the Institute for Clinical and conomic e iew around access to such thera ies ased on a cost eneft mea sure li e cost or uality ad usted life year Finally, almost suggested more aggressi e use management strategies in order to regularly e aluate ris ersus eneft of such thera ies, romot ing discontinuation when ossi le In other treatment categories, use management strategies are a ro riate and e ecti e in con trolling costs ecause multi le thera ies, generics, or iosimilars are a aila le Howe er, for many rare diseases, there are limit ed treatment o tions, so ayers fnd that more aggressi e use management techni ues are not a ro riate

Payers can strategize to e ecti ely manage costs associated with treating rare diseases for exam le, creating a rare disease s ecial ist with ex erience across se eral rare diseases may e alua le in wor ing with case managers to re ent direct costs and guide atients to a ro riate s ecialists ith each no el rare disease treatment a ro al, ayers may ha e to ree aluate the e ect on udgets, which can e challenging or ing colla orati ely with manufacturers to de elo inno ati e contracts may e an o tion to limit ris , es ecially in the initial years after roduct launch Mo ing forward, the strategy for e ecti ely managing this treat ment category will li ely e to see the right ayment a roach that will ensure the atient has access to necessary treatments

RARE NEUROMUSCULAR DISEASES |

Table 1. DMD Pipeline2

Table 2. ALS Pipeline2

HD Pipeline2

three

References

Henderson, endy he Cost of Neuromuscular Disorders in the S Muscular Dystro hy News oday, June , , htt s musculardystro hynews com cost illness neuromuscular diseases united states

IPD Analytics htt s i danalytics com

Birn rant, Da id et al Diagnosis and management of Duchenne muscular dystro hy, art diagnosis, and neuromuscular, reha ilitation, endocrine, and gastrointestinal and nutritional management he ancet Neurology, March , , htt s www thelancet com ournals laneur article PIIS fulltext

Birn rant, Da id et al Diagnosis and management of Duchenne muscular dystro hy, art res iratory, cardiac, one health, and ortho aedic management he ancet Neurology, A ril , , htt s www thelancet com ournals laneur article PIIS fulltext

xondys ac age insert Cam ridge, MA Sare ta hera eutics July

Vyondys ac age insert Cam ridge, MA Sare ta hera eutics Decem er

Amyotro hic ateral Sclerosis A S Fact Sheet National Institute of Neurological Disorders and Stro e, June , htt s www ninds nih go Disorders Patient Caregi er ducation Fact Sheets Amyotro hic ateral Sclerosis A S Fact Sheet text A S is rimarily diagnosed ased,the resence of the disease

Mercuri, ugenio et al Diagnosis and management of s inal muscular atro hy art ecommendations for diagnosis, reha ilitation, ortho edic and nutritional care Neuromuscular Disorders, Fe , , htt s www nmd ournal com article S a stract

Fin el, ichard et al Diagnosis and management of s inal muscular atro hy art Pulmonary and acute care medications, su lements, and immunizations other organ systems and ethics Neuromuscular Disorders, March , htt s reader else ier com reader sd ii S to en BB AD F D B C C F F C C D D A DF B D A A A D F

S inraza® ac age insert Cam ridge, MA Biogen June olgensma® ac age insert Bannoc urn, I A e is July

A ro ed reatments for Huntington s Disease Huntington s Disease News, htt s huntingtonsdiseasenews com a ro ed treatments for huntingtons disease ero, atiana and Jose ey etra enazine enazine , An FDA A ro ed reatment O tion for Huntington s Disease elated Chorea P& , Decem er , htt s www nc i nlm nih go mc articles PMC

FDA a ro es e a s Huntington s disease drug at second attem t PM i e, A ril , htt www mli e com harma news fda a ro es te as huntingtons disease drug at second attem t

Bell, Jaco Neurocrine s Ingrezza secures FDA a ro al BioPharma Di e, A r , , htt s www io harmadi e com news neurocrine fda a ro al ingrezza

Pathways for Paying for are Disease reatments Journal of Clinical Pathways, , htt s www ournalofclinical athways com article athways aying rare disease treatments

Su el, ayt Balancing the Costs of are Disease reatment Managed Healthcare xecuti e, June , , htt s www managedhealthcareexecuti e com iew alancing costs rare disease treatment

Table 3. SMA Pipeline2

Table 4.

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IV Iron:

Managed Care Im lications

As the mar et for IV iron grows, ayers can strategize to e ecti ely manage outcomes, s end, and utilization

Matt Corley, R.Ph. Product Development Director, Medical Pharmacy Strategy Magellan Rx Management

Jef Januska, Pharm.D. Director of Pharmacy Services CenCal Health

Iron defciency occurs when the ody s need for iron is not met ia a sor tion from a erson s diet he discre ancy etween need and a sor tion can e attri uted to a num er of factors, including dietary inta e, oor a sor tion, or hysiologic loss Anemia secondary to iron defciency IDA is the most common form of anemia and is a result of inade uate iron stores for creation of healthy red lood cells IDA is ty ically not considered an end diagnosis, and the atient s wor u is incom lete until the underlying cause has een identifed

Patient o ulations at higher ris for anemia include those demonstrating sym toms of ica, restless legs, regnancy, oncology atients, and chronic idney atients Additionally, atients should e e aluated for sources of iron defciency to address any underlying conditions

An analysis of the glo al urden of anemia showed that while the incidence of IDA decreased, it remained the rimary dri er of cases from to for irtually all study o ulation su sets he American Family Physician u lished its recommendations and noted that the re alence of IDA totals in adult men, to in non His anic white women, and nearly in lac and Mexican American women

Diagnosis

aluation of com lete lood count CBC , red lood cell BC indices, and iron studies should e erformed in adults with unex lained anemia, articularly those with new onset anemia, in order to e aluate for iron defciency See a le for a rea down of la results found within iron defciency de elo ment

Economic Burden of Anemia

he direct and indirect costs of anemia are difcult to defne due to the multifactorial nature of the condition itself and the many rimary conditions associated with it oo ing at oncology s ecifc

Table

Laboratory Findings During the Development of Iron Defciency3

Drug Normal Iron defciency without anemia Iron defciency with mild anemia

Severe iron defciency with severe anemia

Hemoglo in Normal range Normal range to g d to g to g d to g

ed lood cell size and a earance Normal Normal

Serum ferritin to ng m

Normal or slight hy ochromia

Microcytosis and hy o chromia

Serum iron to mcg d to mcg d mcg d mcg d

otal iron inding ca acity transferrin to mcg d to mcg d to mcg d mcg d

ransferrin saturation to eticulocyte hemoglo in to g to g to g Data not a aila le

Bone marrow iron stainAde uate iron resentIron a sent Iron a sent Iron a sent

rythrocyte zinc roto or hyrin to ng ml BC to ng ml BC ng ml BC to ng ml BC

*The normal range for hemoglobin varies by age and sex (adult men, 14 to 17.5 g/dL; adult women, 12.3 to 15.3 g/dL). ¶The exact value is not well established; some clinicians may use a lower value for diagnosing iron defciency.

atients to narrow the sco e, a re iew of two dozen studies noted that anemia treatments associated with these atients were estimated to e etween , and , SD ith the a ro als of Feraheme® , AMAG Pharmaceuticals , In ectafer® , American egent , and Monoferric® , Pharmacosmos hera eutics , the treatment cost has increased

he a erage wholesale ac uisition cost AC er treatment cycle of the three agents in the initial analysis is s , for the treatments most recently a ro ed see a le

Therapy Options: Oral vs. IV

egardless of the resence of sym toms, atients with IDA should e treated to a oid otential organ damage, ischemia, and rogression of the anemia reatment ty ically continues until the underlying cause is addressed or the atient s iron stores regain ade uate le els

With several more recent approvals in the space, the treatment cost has increased.

hether the thera y is oral or intra enous IV iron de ends on the se erity of the anemia, cost of treatment, a aila ility of different roducts, and the atient s tolerance for oral iron Patients with uncom licated IDA are generally started with oral iron More recent ractice guidelines suggest that lower and less fre uent dosing of oral agents, such as three times wee ly, is associated with etter outcomes and im ro ed tolera ility , Similar dosing strategies are eing ex lored with esta lished IV agents All oral agent o tions are considered e ually e ecti e when ta en as directed For atients with com lex disease, a history of intolerance

1.

J INFeD

J Ferrlecit

Daily, as needed to correct defciency

Daily, until corrected u to

J Venofer o er wee s

J In ectafer wee ly

Feraheme , , gi en days a art

J Monoferric , ,

The combination of novel product development — particularly intravenous supplements — and increased use in oncology, renal, gastrointestinal, and gynecological conditions is expected to continue to increase the use of IV iron.

to oral agents, oor a sor tion of oral agents, or who are resenting in a manner that re uires more urgent correction, IV thera y is an a ro riate o tion e lenishing de leted iron stores with oral treatment ta es at least three or more months, whereas if the rimary cause of defciency is addressed, iron stores can usually e re lenished with a single IV dose

arly IV iron roducts, such as high molecular weight iron dextran, were associated with life threatening reactions and ha e een remo ed from the S mar et A aila le roducts are considered to e e ually e ecti e at re lenishing iron stores , he rimary di erentiators etween IV roducts are cost and num er of administrations needed to treat see a le For low molecular weight iron dextran INFeD® , a test dose is also needed Contraindications, warnings, and recautions for the f e non dextran roducts are similar and include cautions for iron o erload, hy otension, and hy ersensiti ity reactions

Table 2. IDA Treatment Costs

Awareness

he com ination of no el roduct de elo ment articularly intra enous su lements and increased use in oncology, renal, gastrointestinal, and gynecological conditions is ex ected to continue to increase the use of IV iron Newer roducts o er con enience ut at a remium cost Agents a ro ed since are, on a erage, six times more costly er treatment cycle than the roducts a ro ed rior to Neertheless, CMS has a reciated the clinical alue of IV iron re lacement and has made IV iron a frst line treatment for some conditions within its Medicare rogram he com ination of a s yroc eting cost to treat and increased relati e atient counts may cause ayers to rioritize e ecti e management in this s ace On the atient side, those whose enefts include a co share of the costs to treat can e faced with considera le fnancial urden

Surveillance and Strategies

ith a growing IV iron mar et, o ortunities may soon arise that were not re iously a aila le due to a lac of com etition, relati e consistency in s end among roducts, and changing strategies for diagnosing and treating these atients

Plans that monitor their current IV iron s end, utilization trends o er time, and mar et share of the a aila le agents could de elo strategies tailored to the o ulation they ser ice, ta e regional idiosyncrasies into account, facilitate access to referred roducts, and ta e ad antage of ricing dis arities when a ro riate

References

asse aum, Nicholas et al A systematic analysis of glo al anemia urden from to Blood , illi , Shersten et al Iron Defciency Anemia Am Fam Physician, March ,

Buttarello, Mauro et al aluation of the hy ochromic erythrocyte and reticulocyte hemoglo in content ro ided y the Sysmex analyzer in diagnosis of iron defciency erythro oiesis Clin Chem a Med, Decem er , iou, S et al conomic urden of haematological ad erse e ects in cancer atients a systematic re iew Clin Drug In estig

Schrier, Stanley So you now how to treat iron defciency anemia Blood, Octo er ,

Auer ach, Michael and Stanley Schrier reatment of iron defciency is getting trendy ancet Haematol e u Oct

Auer ach, Michael and homas Deloughery Single dose intra enous iron for iron defciency a new aradigm Hematology Am Soc Hematol duc Program Decem er ,

Auer ach, Michael and John Adamson How we diagnose and treat iron defciency anemia Am J Hematol ,

A dulrehman, Jameel et al he safety and efcacy of ferumoxytol in the treatment of iron defciency a systematic re iew and meta analysis ransfusion , u No

(NUPLAZID®)Acadia

pembrolizumab (KEYTRUDA®)Merck

Esophageal cancer (locally advanced/ metastatic, 1st line, in combination with platinum- and uoro yrimidine ased chemotherapy)

lorlatinib (LORBRENA®) Pfzer

(1st line, ALKpositive)

pegunigalsidase alfa Chiesi Fabry Disease

tenapanor (IBSRELA®) Ardelyx

abrocitinib Pfzer

(dialysis-dependent patient)

dermatitis/ eczema

Treprostinil (TYVASO®) United Therapeutics Interstitial lung diseaseassociated pulmonary hypertension InhaledsNDA April 2021

teri unomide A BAGIO®) Sanof

nivolumab (OPDIVO®) Bristol Myers Squibb

Esophageal/ gastroesophageal junction cancer (resected, adjuvant setting, after neoadjuvant chemoradiation therapy)

loncastuximab tesirine ADC Therapeutics Di use large B cell lymphoma (relapsed/ refractory)

nivolumab (OPDIVO®) Bristol Myers Squibb

Gastric cancer (advanced/metastatic, in combination with uoro yrimidine and platinum-based chemotherapy)

dehydrated alcohol Eton Pharmaceuticals Methanol poisoningSQ

leuprolide mesylate ready-to-use, six-month depot Foresee PharmaceuticalsProstate cancer

belumosudil Kadmon Corporation Graft versus host disease (chronic)

ozanimod (ZEPOSIA®) Bristol Myers Squibb

pirfenidone (Esbriet®) Genentech Interstitial lung diseasePO

priority review5/20/2021

orphan drug; priority review 5/21/2021

sBLA; priority review5/25/2021

orphan drug5/27/2021

5/27/2021

NDA; breakthrough therapy; orphan drug; priority review; Project Orbis; real-time oncology review 5/28/2021

breakthrough therapy; orphan drug; priority review May 2021

ibrexafungerp SCYNEXIS Vulvovaginal candidiasisPO NDA; fast track; orphan drug ualifed infectious drug product; priority review 6/1/2021

semaglutide (Ozempic®) Novo Nordisk Obesity

sNDA; priority review6/4/2021

plasminogen (human) Liminal BioSciences HypoplasminogenemiaIV BLA; fast track; orphan drug; rare pediatric disease 6/5/2021

aducanumab Biogen/Eisai Alzheimer’s diseaseIV

Elexacaftor/tezacaftor/ivacaftor (TRIKAFTA®) Vertex Pharmaceuticals Cystic f rosis ages to 11, >F508del mutation) PO

umbralisib TG Therapeutics Follicular lymphoma (>2 prior systemic therapies)

breakthrough therapy; orphan drug; priority review 6/8/2021

orphan drug 6/15/2021

tofacitinib (XELJANZ®; XELJANZ XR®) Pfzer

aspart (biosimilar to Novo-Log®)

20-valeant pneumococcal conjugate vaccine Pfzer

pneumoniae vaccines (antibacterial)

avacopan ChemoCentryx

vasculitis

15-valent pneumococcal conjugate vaccine Merck Invasive pneumococcal disease prevention

narsoplimab Omeros Hematopoietic stem cell transplantassociated thrombotic microangiopathy

odevixibat Albireo Pharma

familial intrahepatic cholestasisrelated pruritus

sulopenem etzadroxil/probenecidIterum Therapeutics UTI (uncomplicated, quinolone-resistant)

bimekizumab

Abbreviations: ANCA = antineutrophil cytoplasmic antibodies; BLA = biologics license application; CKD = chronic kidney disease; IM = intramuscular; IV = intravenous; MoCD = molybdenum cofactor defciency MS multi le sclerosis NDA new drug a lication NSC C non small cell lung cancer PA soriatic arthritis PNH aroxysmal nocturnal hemoglo inuria PO oral sBLA = supplemental biologics application; SLE = systemic lupus erythematosus; sNDA = supplemental new drug application; SQ = subcutaneous; TBE = tick-borne encephalitis; T1DM = type 1 diabetes mellitus; T2DM = type 2 diabetes mellitus; TD = transdermal; UC = ulcerative colitis; UTI = urinary tract infection

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